PROJECT SUMMARY Parkinson?s disease (PD) is a severe, irreversible neurodegenerative disease that involves asymmetric symptoms. For most patients (over 85%) motor symptoms begin on one side of the body. This motor asymmetry is so characteristic of PD that it is often used as a clinical parameter to differentiate PD from similar syndromes. Though motor symptoms gradually become bilateral as the disease progresses, the initial asymmetry remains stable and persists even at advanced disease stages. Lateralization in PD has been linked to rate of disease progression and differences in the presentation of non-motor symptoms, including cognitive symptoms. Symptom asymmetry in PD is the direct result of hemisphere differences in subcortical and cortical neuronal dysfunction and loss. Despite the prevalence of asymmetric brain changes in PD and its importance to clinical manifestations, the factors rendering neurons more vulnerable in one brain hemisphere over the other remain one the most enigmatic puzzles of PD. The goal of this study is to determine the molecular signatures enabling hemisphere differences in neuronal dysfunction and symptom asymmetry in PD. In PD, both the development of neuropathology and the progressive loss of neurons involve abnormalities in gene regulation. We have recently found evidence that hemisphere asymmetry in PD neurons involves differences in epigenetic marks that relate to transcriptional states. We have also found that neuronal epigenomes across hemispheres change with aging, a process that is accelerated in PD. Therefore, we propose that hemisphere differences in epigenetic regulation of genes could underlie the asymmetry in neuronal impairment, which in turn impacts symptom lateralization. This project involves cutting-edge techniques in epigenomics and adjoining transcriptomic and genetic analyses in isolated brain neurons of PD patients and controls. We also determine the impact of aging, rate of progression, and PD pathology on the development of hemisphere asymmetry. Our project will define (i) the extent of hemisphere asymmetry in the epigenome in neurons of PD patients, its effect on gene expression, and its relevance to symptom lateralization, (ii) the divergence of the epigenome across hemispheres with aging, and (iii) the capacity for PD neuropathology to induce epigenetic and transcriptional changes relevant to hemisphere asymmetry in vivo. This work will identify the genes involved in asymmetric neuronal dysfunction in PD. Uncovering the mechanisms involved in asymmetric brain changes in PD is important for understanding the biological basis of symptom lateralization in PD. This work also provides fundamental insight on the degree of molecular asymmetry across hemispheres of the human brain.